Mercaptobenzimidazolyl ureas and thioureas

ABSTRACT

Mercaptobenzimidazolyl ureas and thioureas are provided having the structure   and which are useful as anthelmintic agents.

United States Patent [1 1 Narayanan et al.

[4 1 Aug. 26, 1975 MERCAPTOBENZIMIDAZOLYL UREAS AND THIOUREAS [75] Inventors: Venkatachala Lakshmi Narayanan,

Hightstown; Rudiger Dieter Haugwitz, Titusville, both of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: Jan. 18, 1974 [2]] App]. No.: 434,714

Related U.S. Application Data [63] Continuation-impart of Ser. No. 312,004, Dec. 4, 1972, abandoned, which is a continuation-in-part of UNITED STATES PATENTS 3,720,686 3/I973 Narayanan et al 260/3092 Primary Examiner-Sherman D. Winters Assistant ExaminerS. D. Winters Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith; Stephen B. Davis [57] ABSTRACT Mercaptobenzimidazolyl ureas and thioureas are provided having the structure and which are useful as anthelmintic agents.

10 Claims, No Drawings MERCAPTOBENZIMIDAZOLYL UREAS AND THIOUREAS This application is a continuation-in-part of copending application Ser. No. 312,004. filed Dec. 4, 1972, now abandoned which in turn was a continuation-inpart of application Ser. No. 136.197 filed Apr. 2|. I971, now US. Pat. No. 3.718.662.

The present invention relates to mercaptobenzimidazolyl ureas and thioureas having the structure N I c=x' wherein X is oxygen or sulfur. R is hydrogen, lower alkyl, aryl. aralkyl. lower alkoxy, aroyl, substituted aryl, lower alkylthio. acyl. trifluoromethyl. nitro, halogen, cyano. thiocyanato. amido, substituted amino. dialkylaminoalkyl, alkyloxyor aryloxycarbonyl wherein R; can be lower alkyl, lower alkylaryl) or carbamate ester (-NHCOOR, wherein R is lower alkyl.

aryl, substituted aryl or cycloalkyl, R, is aryl, substituted aryl. cycloalkyl, lower alkyl, acyl or aroyl, Z is lower alkyl, aryl. lower alkoxy. aryloxy, lower alkylamino. cycloalkylamino of 3 to 7 carbons. acyl amino, or aryl amino. Y is a straight chain alkylene group of' from one to six carbon atoms which may or may not be substituted by one or two alkyl groups of from one to four carbon atoms. 1: is t). l or 2. and X is oxygen when Z is lower alkoxy. aryloxy, aryl. or lower alkyl and is either oxygen or sulfur when Z is lower alkylamino, cycloalkylamino. acyl amino, or aryl amino.

The lower alkyl groups set forth above include straight or branched chain aliphatic hydrocarbon radicals having up to and including seven carbon atoms. such as methyl. ethyl, propyl, isopropyl. butyl. s-butyl, isobutyl. t-butyl. amyl. hexyl. heptyl. and the like.

The alkylene group represents a divalent straight or branched chain aliphatic hydrocarbon and can contain from one to six carbon atoms in a chain with or without side chains. The side chains are generally from one to four carbon atoms which may also be straight or branched. The side chains can include cycloalkyl substituents. Examples of these groups include groups corresponding-to the above alkyl groups as well as 3-(cy clobutyhbutylene. Z-ethylpropylene. butylene and 2- cycIopropylhexylenc.

The lower alkoxy group and the alkoxy portion of the alkoxycarbonyl group include straight and branched chain radicals of up to and including seven carbon atoms, corresponding to the above alkyl groups, e.g., methoxy. ethoxy. propoxy, isopropoxy, and the like. The aryloxy portion of the aryloxycarbonyl group in cludes any of the aryl groups set out below.

The cycloalkyl groups can have from three to about seven carbon atoms and include, for example, cyclopropyl, eyclopentyl and cycloheptyl.

The term halogen includes each of the four halogens, but fluorine and chlorine are preferred.

The substituted amino groups include monoor dilower alkylor arylamino where lower alkyl and aryl are as defined herein, such as methylamino. ethylamino, isopropylamine, heptylamino, dimethylamino, diethylamino, ethylmethylamino, butylmethylamino, ethyl i-propylamino. aniline, diphenylamino, napthylamino, or N-methyl-N-phenylamino and the like.

The term "aryl" includes monocyclic or bicyclic monovalent aromatic ring systems such as phenyl or naphthyl. These aryl radicals can include as substituents halogen. nitro or any of the alkyl groups mentioned hereinbefore.

The acyl and aroyl groups included herein are derived from hydrocarbon carboxylic acids of less than twelve carbon atoms, which may be exemplified by the lower alkanoic acids (e.g., formic, acetic, propionic, butyric, valeric). the lower alkenoic acids (e.g., acrylic, methacrylic, crontonic, 3-butenoic and senecioic acids), the monocyclic aryl-carboxylic acids (e.g., benzoic and toluic acids), the monocyclic aryl-lower alkanoic acids {e.g., phenacetic, B-phenylpropionic, a-phenylbutyric. and 5-(p-methylphenyl)-pentanoic acids]. the cycloalkyl carboxylic acids (e.g., cyclobutane carboxylic acid, cyclopentane carboxylic acid and cyclohexane carboxylic acid), the cycloalkenyl carboxylic acids (eg, Z-cyclobutene carboxylic acid and 3- cyclopentene carboxylic acid), the cycloalkyl and cycloalkenyl-lower alkanoic acids [e.g.. cyclohexanew.

cetic, a-cyclopentanebutyric, Z-cyclopenteneacetic and 3-(3-cyclohexene)-pentenoic acid], and the like.

Preferred embodiments of this invention are as follows:

R is hydrogen. lower alkyl. lower alkoxy, lower alkylthio. trifluoromethyl. nitro. halogen, lower alkylamino or di-lower alkylamino.

n is zero or one.

R, is phenyl, substituted phenyl, cycloalkyl, or lower alkyl.

Z is lower alkoxy. phenoxy. substituted phenoxy, lower alkylamino, cycloalkylamino of three to seven carbons. anilino. or substituted anilino.

The most preferred embodiments are as follows:

R is hydrogen or nitro.

R is phenyl. p-nitro-phenyl, or cyclohexyl.

Z is lower alkylamino. cycloalkylamino of three to seven carbons, anilino. or substituted anilino. especially eyclohexylamino.

Examples of compounds falling within the present invention include. but are not limited to, the following set out in Table A below.

Compounds of Formula I can be prepared by reactsuch as benzene, toluene and xylene. Compound IV IS ing a mercaptobenzimidazole of the structure reacted in a molar ratio to compound V (lVzV) of within the range of from about l.5:l to about I: l preferably 1:1.

5 Compounds of Formula I where (R H n I (Z m is carbamoyl or thiocarbamoyl with a haloalkylamine hydrobromide of the structure 6 A Y NH- HBr lll R,NH(| wherein A is Br or Cl employing a molar ratio of llzlll 15 of within the range of from about l5:l to about l:l are prepared by reacting a compound of the formula:

l SY- NH*CNHR v R) N l H and preferably hi to form an aminoalkylthiobenwith an isocyanate or isothiocyanate of the structure zimidazole of the structure R,N=( \ll (mm S-Y-NH where R is acyl. lower alkyl, cycloalkyl of three to seven carbons. or arylr Where l IV R,NHC The reaction of II and Ill is carried out in protic or aprotic solvents such as LllkllllUlS of up to nine carbon atoms, acetone. benzene and tetrahydroluran employing temperatures of within the range of from about to about 150C and preferably from about to about C-NHR,. C. for periods ranging from 30 minutes to about 24 hours and preferably from about 30 minutes to about 5 ll] hours (ompound IV can then be reacted with an isocya mile or isothiocyanate ol' the structure is the same as a molar ratio ofVlzVll within the range of from about 1:1 to about l:5(l and preferably from about 1:2 to about lz5 is utilized. Such compounds (i.e.. where y 0 R'N=( v R.NH(

is the same as to form compounds of Formula Vl. This reaction is carried out at a temperature ranging from about 0 to about C and preferably from about 20 to about 90C. for periods ranging from about 30 minutes to about 24 hours and preferabl from about 3U minutes to about 12 hours in the presence of solvents such as alkanols of up to nine carbon atoms. esters such as are preferably prepared by reacting a compound olthe ethyl acetate, ethcrs such as tetrahydrofuran. ketones structure IV with an excess ol isocyanate or isothiosuch as cth lmcth ketone and aromatic hydrocarbons cyanate Vll. Where 7 8 T Examples of suitable starting o-phenylenediamines ll RNHCL are set out in Table B below is other than TABLE B (-NHR,.

a molar ratio of Vl:Vll of from about 1:] to about l:5() and preferably about 1:] is employed Any of the solvents mentioned above with respect to the reaction of It) compounds IV and V can be employed, The reaction of VI and V" is carried out at a temperature within the range of from about 0 to about I4()C and preferably from about to about 90C for periods ranging from about minutes to about 24 hours and preferably l5 from about 30 minutes to about 12 hours. lv

(ompounds of Formula I where x ll 20 1 l L 4 l S. 2 is alkoxycarbonyl, aryloxycarbonyl. acyl or aroyl can 6 I 3e prepared by reacting compound Vl with a halide of 7. (4| ihe structure z r 1 9 X H (4, 1 1| VII! in, (F1, Z-(--hal ll. (H 5 13 I (,H (5 where l2 (,H,, 5, I is. NO (5) u 14, -SCN ml l r I5. (I 14) 2 m. -,("H (4 1 s alkoxycarbonyl aryloxycarbonyl. acyl or aroyl, in the 2 a r. l resence of a basic catalyst, such as triethylamme, 35 t, CHFCH '4) I -J Ndimethylaniline or N-ethylpiperidme in the presl 1 nce ol a solvent such as employed in the reaction of CHI (4, I ompounds IV and V. A molar ratio of VlzVlll within 2|. NHCOOC H, 15) l he range of from about 1:1 to about l:l()() and prefer- (XX'HB (6) I bly from about 1:] to about M20 is employed. The re- 40 ction is carried out at a temperature within the range 2. -NH(U() (7) ffrom about IS to about 120C and preferably from bout 20 to about 80C for periods ranging from about 5 minutes to about 8 hours and preferably from about U minutes to about 6 hours.

The mercaptoben7imidazole II starting material can a prepared by reacting o phenvlenediumine Examples of suitable haloalkylamine hydrobromides lll include, but are not limited to, the following:

Br(CH J NH HBr (R) n lir- (H. (H-NH HBr ith. for example, potassium, ethyl xanthate in accor- (m nice with the procedure described in Organic Synesis" Col. Vol. IV page 569 to form the mercapbcnzimidazole ll m (Ha Examples of suitable isocyanates and isothiocyanates include. but are not limited to. the following:

The mercaptobenzimidazolyl ureas and thioureas described herein have anthelmintic activity and are useful in the treatment and/or prevention of helminthiasis. a parasitic disease which causes widespread and often serious infection in domesticated animals such as swine. horses. cattle. sheep and goats. In treating domesticated animals. the compounds may be mixed with a nontoxic. edible carrier to form a feed supplement which is then incorporated in the animal feed in the desired concentration. or they may be administered in unit dosage forms which. in the case of large domesti cated animals. take the form of boluses. or in the form of a liquid drench. Alternatively. water-soluble salts or a dispersable. wettable powder containing the anthelmintic agent may be added to the drinking water of the animals.

Lit

(all

The preferred dosage level for treating a helminth infection will depend to a large extent on the particular mercaptobenzimidazolyl urea or thiourea being employed. on the severity of the infection and on the particular species of animal to be treated. In general. the mercaptobenzimidazolyl ureas and thioureas exhibit anthelmintic activity when administered to animals in a daily dose of about 50 to about 300 mg. per kilogram of animal body weight. It is preferred to employ in the range of 100-200 mg. per kilogram of body weight per day. The compounds may be given in a single dose or divided into a plurality of smaller doses. If desired. the course of treatment may be extended over a period of days in which case the optimum daily dose level may be lowered. When the compounds are to be employed primarily as prophylactic agents for the prevention of helminthic infections, the preferred daily dose level is. of course. lower than the therapeutic level is. preferably in the range of about l()70 mg. per kilogram of body weight. The mercaptobenzimidazolyl ureas and thioureas may be incorporated in the animal feeds. and this method of administration is preferred when the compounds are to be used prophylacetically. in which case they are incorporated in the feeds at concentrations such that the animal will consume daily from about It) to about 70 mg. of mercaptobenzimidazolyl urea or thiourea per kilogram of body weight.

The means employed for administering these mer captobenzimidazolyl ureas and thioureas to animals are not critical. and any of the methods now used or avail able for treating animals infected with or susceptible to parasitic infections are satisfactory. When these substances are employed therapeutically to treat an estab lished infection. they are conveniently administered in a unit dosage form such as in a capsule. bolus. tablet. or as a liquid drench. It will be noted that all of these methods contemplate oral administration. since this is the most effective method of treating the worminfested stomach or intestinal tract.

The following Examples further illustrate the invention.

EXAMPLE 1 l-[ 3-( 2-Benzimidazolylthio )propyl l-3-phenyl-2- thiourea A. 2-[( 3-Aminopropyl )thio1benzimidazole. dihydrobromide To a solution of 10 g of Z-mercaptobenzimidazole in l5 ml of ethyl alcohol. a solution of l5.l g of 3 bromopropylamine hydrohromide in ml of water is added and the mixture is refluxed for 3 hours. The solvent is evaporated in vacuo and the residue is crystallized from absolute alcohol to give l9.l g 7 l7r of needles of the above title. nip. 272274.

Anal. Calcd. for CWHHNHSQHBI'I (132.54: H.155; N.ll.3)". Br.43.3(). Found: c.3231; H.336; N.l l.' Br.43.()8. cB. l-[( 3-( 2-Benzimidazolylthio )propyl |-3- phenyLZ-thiourea To a solution of 5.5 g (0.015 mole) of 2-[ 3- aminopropyll-thio]henzimidazole. dihydrobromide in 50 ml of ethyl alcohol. alcoholic solution of potassium hydroxide is added until slightly basic. Phenyl isothiocyanate. 1.8 g ((HHS mole) is added and the reaction mixture is stirred and refluxed for 1 hour. At the end of this period. the solvent is evaporated in vacuo. and the residue crystallized from dilute methyl alcohol to give 3.() g of the title compound, mp. l6ll63. Recrystallization from dilute methyl alcohol gives an analytical sample, m.p. l63l65.

Anal. Calcd. for C H N O C.59.ol; H.530; N l6.35. Found: (59.63; H.513; N.l6.()8.

EXAMPLE 2 l-[ 3-( Z-Benzimidazolylthio )propy] ]-3-p-nitrophenyl- Z-thiourea Following the procedure of Example IE. but substituting an equivalent amount of p-nitrophenyl isothiocyanate for phenyl isothiocyanate, there is obtained the title compound m.p4 l72l73.

EXAMPLE 3 l-[ 3-! (5-Nitro-Z-benzimidazolyl )thio Ipropyl ]-3-phenyl-2 thiourea Av 5-Nitro-2-[(3-uminopropyl)thio]benzimidu2ole, dihydrobromide Following the procedure of Example IA but substi luting an equivalent amount of 5-nitro2- mercaptobenzimidazole for 2-mercuptobenzimidazole,

B. l-[(3-1l5-Nitro-Z-benzimidazolyl)thiolpropyll-3-phenyIQ-thiourea Following the procedure of Example lB. but substituting an equivalent amount of 5nitro-Z-[(3- aminopropyl) thiol-benzimidamle dihydrohromide for 2-[ 3-uminopropyl) thio l-benzimidazole dihydrobromide, there is obtained the title compound, mlp. l53l55.

Anal Caled. for C H N O C S c.5169; H.442; N IXUB. Found: (52.68; H,4.58; N l7.7(v.

EXAMPLE 4 l-C 'clohex vl3-l 3-H l(cyclohexylcarbamoyl )-5-nitro- Z-benzimidazolyl ]thio Ipropyl lure-a To a solution of 2.5 g (01)] mole) of S-nitro-2-[(3- aminopropyl)thiolbenzimidazole in 50 ml of tetrahydrofuran. 2.5 g (0.02 mole) of cyclohexyl isocyanate is added, and the mixture refluxed for ()5 hour The solvent is evaporated in vacuo, and the residue is crystallized from absolute alcohol to give the title compound, m.p. l55l56.

EXAMPLES 5 to 22 Following the procedure of Example lA except substituting the haloalkylamine hydrobromide shown in column A and the mercuptobenzimidazole shown in column B of Table l below the aminoalkylthiobenzimidazole shown in column C is formed; and then following the procedure of Example [8 substituting the uminoalkylthiobenzimidazole of column C and the isocyanate or isothiocyanate of column D the product shown in column E is formed.

TAB LE l C0ntinued X u (R) SYNH(NH--R T H n P Y R, X M h As in As in As in Column B Column A Column D EXAMPLES 23 to 32 5 and 16 to 22 (column E of Table l) as shown in column A of Table ll and the isocyanate or lsothiocyanute Following the procedure of Example 4 except suhsti shown in column B. the product shown in column C IS tuting the bcnzimidzlzole producls of Examples 1 Z and obtained.

TABLE II N x x N x u u ll (R) S -Y- NH-C NH R, a (R SYNH--( NH-R H c :X I

l1\ ll\ I No n RlPlWllH IH Y X R, N) l, X "R X RJJC-YZ [ll l-Aeetyl-5-Nitro-2-henzimidazolyl Jthio Ipropyl 3-phenyl- 2thioureu To 11 solution of 3.8 g (0.0] mole) of l-l 3-l (S-nitrohenzimidazolyl )thio jpropyl ]-3-phenyl-2thiourez1 in )0 ml oftetrahydrofumn, 11 solution oI'UiXU g of ucetyl iloride in 10 ml of tetruhydrofurun is added followed the addition of l.l ml of triethylaminc. The mixture refluxed for 0.5 hour on a steam bath. The solvent is moved in vacuo and the product crystallized from Lil- )hUl,

compound shown in column B. the product shown in column is obtained TABLE III A B C N N\ ,i (I) SY-NH--C- NH- R, ZCHul (R) S-Y-NH-C-NH-RI u n I c x I H Ex (Ex Nu. n R X R. No.1 )l( R Y X RI n w CZ 34. H :hi- 5 311;. l (THHOCCI As in As in II (olumu B ("olumn A 35. H (('H=l; S N0 (.i 2 CAXHSXBI (I) 367 H -"l -l:' 0 n u 5 u a ll 37 1 N0 (5) -CH-CH, 5 (HR l6 1('H.-|C|=H,CBr

a r n 33, I (h (5| -(H n-CH- 0 Q H C l7 C;.H,0C(f| O (I) 39. cy n cwn CH. 0 l8 CH, OCBr 40. l (CH l N -(CHr S .H,- I) C -,H ,C--Cl 41. lc n mn, ((H s (,H In fH CCl l l 42. 1 (H [5) ((H:l- 0 H,, 21 C.H,,0CC|

43. l NH(()(KH;; (H. 5 (H 22 CH CCI We claim: amino; u is an integer selected from U. l or 2: R is se- 1. A compound of the formulu: lected from the group consisting oflower alkyl, cycloalkyl of 3 to 7 carbons. phenyl. substituted phenyl N s wherein said substituent is nitro, halogen, or lower ulkyl. lower ulkylcurbonyl. und benzoyl; Z is selected from the group consisting of lower alkyl, loweralkoxy, phenyl, phenoxy, substituted phenyl and phenoxy wherein said substituent is halogen. nitro. or lower alkyl, lower ulkylamino. cycloalkylamino of 3 to 7 carbons. unilino. benzylumino, substituted anilino wherein suid substituent is halogen, nitro, or lower alkoxy. lower ulkyleurbonylumido. and phenylcurhonylumido; Y is straight chain alkylene of l to 6 carbons which may or may not be substituted by one or two alkyl groups of from I to 4 carbons; X is selected from the group consisting of oxygen and sulfur; and X is oxygen when 2 is lower zllkyl lower alkoxy, phenyl. phcnoxy substituted phenyl or substituted phenoxy and X is selected from the group consisting ofoxygen and sulfur when 2 is lower ulkylumino, cycloulkylumino of 3 to 7 carbons. unilino. benvylumino. substituted unilino. lower ulkylcurbonylumido, or phenylcarbonylumido.

2. A compound of the formula:

;ubstituted anilino wherein said substituent is selected "rom halogen, nitro and lower allkyl; Y is straight chain llkylene group of from I to 6 carbons which may or nay not be substituted by one or two alkyl groups of 'rom l to 4 carbons, X is selected from the group con- 20 sisting of oxygen and sulfur; and X is oxygen when Z is lower alkoxy phcnoxy, or substituted phenoxy and X is selected from the group consisting of oxygen and sulfur when 2 is lower alkylamino. cycloalkylamino of 3 to 7 carbons anilino, or substituted anilino.

3. The compound of claim 2 wherein Z is selected from the group consisting of lower alkylamino. cycloalkylamino of 3 to 7 carbons, anilino and substituted anilino wherein said suhstituent is selected from the group consisting of halogen. lower alkyl. and nitro.

4. The compound of claim 3 wherein R is selected from the group consisting of hydrogen and nitro; R is selected from the group consisting of phenyl. pnitrophenyl and cyclohexyl; and Y is (CH 5. The compound of claim 4 wherein X and X are both sulfur.

6. The compound of claim 4 whercin X is sulfur and X is oxygen.

7. The compound of claim 4 wherein X is oxygen and X is sulfur.

8. The compound of claim 4 wherein X and X' are both oxygen.

9. The compound ofclaim 8 wherein Z is cyclohexylammo.

10. The compound of claim 9 having the name I- cyclohexyl-3-[ 3-[[ l cyclohexylcarbamoyl )-5 nitro-2- benzimidazolyl lthio ]propyl ]urea.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Page 1 of PATENT NO. 1 3,901,909

DATED Aug. 26 1975 INVENTOMS) V. L. Narayanan et al It is certified that error appears in the ab0ve-iderrtified patent and that said Letters Patent are hereby corrected as shown below:

Col. 2, line 35, "crontonic" should read -crotonic. Table A, each line under the headings should be numbered 1 through 21.

Table A, line 2, under the heading "R should read pNO C H Table A, line 5, under the heading "R(position) should read 4 9 6C H Table A, line 6, under the heading "Z", should read pCH C H NH Table A, line 6, under the heading R ",should read 4 9 Table A, line 8, under the heading "Z", should read C H 4 9 Table A, line 13, under the heading "Z", should read Table A, line 16, under the heading "Y", should read Table A, line 17, under the heading "R should read 4 9" Col. 6, line 15, should read (R NH- Col. 6, formula VII, should read Col. 6, line 40, should read -R NHH UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Page 2 of t PATENT NO. 3,901 .909 DATED Aug. 26 1975 lNVENTORtS) V. L. Narayanan et al It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below,

It should read R NHC Col. 6, line 55,

Col 7, line 1, should read R NHE- Table B, line 7, under the heading "R(position) should read (C H N- (4) Table B, line 12, under the heading "R(position)", should read (C H Table B, line 19, under CH C H (4) Table B, line 22, under the heading "R(position)", should read the heading "R(position)", should read NHCOOC H (6) lS Col. 9, line 12, should read C H NC Col. 9, line 18, should read IS| CH C H NC r. Col. 9, line 41, should read 8 CH C H OCBr Col. 10, line 58, the "0" should be deleted, and the "B" should begin a new paragraph.

Col. 11, line 30, "N,N, 13 .40" should read N, l3.40--.

Table I, examples 5 through 12, a period rather than "3" should follow each example no.

Table I, example 6, col. A, under the heading "Y" should read Table I example 8, col. D, under the heading "R should rea UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Page 3 of A PATENT NO. 1 3,901 ,909

DATED T Aug. 26 1975 lNvENTOR(S) i V. L. Narayanan et al.

It is certified that enor appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Table I, example 10, col. A, under the heading "Y", should read Table I, example 10, col. D, under the heading "R should read pNO C H Table I, example 15, col. B, under the heading "R(position) should read 0 Table I, example 16, col. A, under the heading "Y", should read CCH E Table I, example 20, col. D, under the heading "R should read C Table II, example 23, col. B, should read CH NH O Table II, example 24, col. A, under the heading "R should read pNO C H Table II, example 28, col. B, under the heading "2, should read 0 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION Page 4d 1 PATENT NO. 3 ,90l,909

DATED Aug. 26 1975 INVENTOR(5) 1 V. L. Narayanan et al It is certified that error appears in the above-identified patent and that said Letters F atent are hereby corrected as shown below:

[SEAL] II Table II, example 28, col. C, under the heading "C-Z",

should read Table II, example 30, C01. A, under the heading "R should read C H Table II, example 30, col. B, under the heading "Z", should I read p NO C H NH f? Table II example 30 col C, under the heading "C-Z" should read r p-NO c H NHC- 2 6 4 Table III, example 35, col. A, under the heading "R should read pNO C H Table III, example 37 col B, should read I? pCH C H CBr Table III, example 38, col. A, under the heading "R", should read CH (5) Table III, example 41, 001. A, under the heading "R should read C H O H o cl Table III, example 42, col B, should read C 9 Col. 18, line 51, "loweralkoxy" should read lower alkoxy--. Col. 19, line 25, "allky1"should read alkyl.

A nest:

RUTH C. MASON Arresting Officer C. MARSHALL DANN Commissioner ufParenls and Trademarks 

1. A COMPOUND OF THE FORMULA,
 2. A compound of the formula:
 3. The compound of claim 2 wherein Z is selected from the group consisting of lower alkylamino, cycloalkylamino of 3 to 7 carbons, anilino, and substituted anilino wherein said substituent is selected from the group consisting of halogen, lower alkyl, and nitro.
 4. The compound of claim 3 wherein R is selected from the group consisting of hydrogen and nitro; R1 is selected from the group consisting of phenyl, p-nitrophenyl and cyclohexyl; and Y is -(CH2)3-.
 5. The compound of claim 4 wherein X and X'' are both sulfur.
 6. The compound of claim 4 wherein X is sulfur and X'' is oxygen.
 7. The compound of claim 4 wherein X is oxygen and X'' is sulfur.
 8. The compound of claim 4 wherein X and X'' are both oxygen.
 9. The compound of claim 8 wherein Z is cyclohexylamino.
 10. The compound of claim 9 having the name 1-cyclohexyl-3-(3-((1-(cyclohexylcarbamoyl)-5-nitro-2 -benzimidazolyl)thio)propyl)urea. 